A cancer treatment method may be largely divided into surgery, radiotherapy, and chemotherapy, and currently, in Korea, the number of cancer patients receiving the radiotherapy has increased every year and thus, the importance of the radiotherapy in the cancer treatment has also increased.
The radiotherapy is known as an essential treatment method in various kinds of cancers, but it has been pointed out as problems in that radiation resistance of the cancer cells is obtained and efficiency in the radiotherapy is deteriorated by the damage to normal tissues in radiotherapy with a high radiation dose. Accordingly, researches on a radiation sensitizer for enhancing efficiency of the radiotherapy have been attempted, but the radiation sensitizers which have been reported until the present are mainly anticancer agents, and for example, taxol, cisplatin, and the like have been reported.
Further, a radiotherapy enhancer which has no property as an anticancer and is used only in the radiotherapy is tirapazamine, but it is known that the tirapazamine has an effect on only hypoxic tumor cells and has a marginal effect on clinical radiotherapy because drug delivery to the inside of the tumor tissue is in adequate due to tumor-specific internal pressure in hypoxia.
However, when the anticancer agents used for enhancing the radiotherapy effect is combined with the radiotherapy, toxicity of the anticancer agents may be complicatedly shown with side effects shown in the radiotherapy, that is, inflammation of the radiotherapy site, gastroenteric trouble, nausea, vomiting, and diarrhea. Particularly, cancers in the central nervous system are caused from other cell series including glia such as astrocytes and oligodendrocytes. Astrocytic tumor (astrocytomas) may be divided into diffuse astrocytoma and localized astrocytoma according to an interaction with adjacent microenvironments. The localized astrocytoma has proliferation having a clear interface with the ambient microenvironment and limited potential infiltration, while the diffuse astrocytoma has a characteristic of cellular infiltration far away from peritumoral margin and a main tumor formation site regardless of a tumor grade. The diffuse astrocytoma is classified into three types of astrocytoma (World Health Organization [WHO] grade), anaplastic astrocytoma (WHO grade), and glioblastoma multiform (GBM, WHO grade). The diffuse astrocytoma having the three grades has an infiltration characteristic, and particularly, glioma (GBM) has characteristics of higher proliferation, necrosis and hypoxia, angiogenesis, high infiltration to a support structure of the brain, and high cancer recurrence rate. Since transition to other tissues is easy, various attempts for enhancing cancer treatment efficiency thereof have been conducted, but there is a problem in that there is a limitation only in the chemotherapy, and even in the radiotherapy, the cancer cells are not treated well by obtaining radiation resistance.
Further, in the brain tumor treatment, the radiotherapy in addition to surgical treatment and chemotherapy is an important treatment method. Among the brain tumors, in GBM brain tumor patients as the WHO grade, prognosis (cancer recurrence) is not good and an average survival rate is one year and a 5-year survival rate is less than 5% in spite of surgical therapy, chemotherapy, radiotherapy, or complicated therapy (e.g. radiotherapy and chemotherapy or surgical therapy and radiotherapy). Among the brain tumor treatment methods, the radiotherapy is a method of removing abnormal cells by delaying a cell cycle (DNA damage checkpoint) or inducing apoptosis with respect to the DNA damage caused by the radiation. However, there are problems of the radiotherapy in that radiation-resistive cancer cells cause recurrence of the cancer due to inherent radiation resistance of the cancer cells and an increase in resistance according to the radiotherapy and radiation-resistive cells have resistance to the anticancer agents.
Accordingly, development of radiation sensitivity enhancers capable of minimizing side effects and optimizing radiotherapy while enhancing the radiation sensitivity to the cancer cells having inherent radiation resistance has been urgently required.
Meanwhile, phosphoinositide (PI) of a cell membrane regulates various cell functions such as cell proliferation, receptor signal transduction, cytoskeletal rearrangement, and motility. In the human cells, phosphatidylinositol 4-phosphate (PI4P) is generated by a phosphatidylinositol 4 kinase (PI4K), and the PI4K has IIα, IIβ, IIIα, and IIIβ as four isozymes. The PI4P generated by the PI4K is a required substance for two types of PI-dependent signaling systems, that is, a phospholipase C (PLC)-PKC signaling system and a phosphoinositide 3-kinase (PI3K)-Akt signaling system which regulate cell proliferation and movement. Accordingly, propagation of the PI4P is interrupted through inhibition of the PI4K to become a useful treatment strategy capable of simultaneously inhibiting PLC and PI3K signal transduction in the reception activation signal process.
Over the last 20 years, in the cancers, a role of the PI3K signaling is very actively verified to be highlighted as a major target of the anticancer treatment together with discovery of phosphatase and tensin homolog (PTEN), and various drugs are developed and clinically implemented, while the role of the PI4K in the cancer does not receive proper attention.
Recently, based on universities and research institutes in United States and England, while the above research results that the PI4K plays an important role in occurrence of specific cancers start to be reported, attempts to investigate new roles of PI4K in occurrence, progression, and treatment of the cancer are being reviewed, but mostly remain in a barren state as an initial stage of the researches.
Meanwhile, it is known that 4-anilino quinazoline as a replication inhibitor of hepatitis C virus has no mechanism which is clearly found, but has an antiviral effect by targeting a virus protein NS5A. Recently, it is reported that PI4K-IIIα is a host factor for replication of the hepatitis C virus, and a research on a mechanism that AL-9 as one of a 4-anilino quinazoline compound inhibits the PI4K-IIIα to have an antiviral effect is reported.
Direct-acting antiviral agents (DAA) are drugs which directly act to HCV virus, and availability and stability thereof have already been verified through clinical experiments. Particularly, as compared with peginterferon alpha and ribavirin which have been used as standard therapy to the hepatitis C virus, in spite of side effects of hardness, a similar or excellent therapeutic response is reported and included in care recommendations in the liver academy in US and Europe.
As a result, the inventors conducted researches for developing a new composition for enhancing radiation sensitivity and verified that PI4K isozyme-specific siRNA and antiviral agent as PI4K isozyme inhibitors are treated to have an excellent effect of enhancing radiation sensitivity such as reducing viability of the cancer cells and radiation resistance during in radiation irradiation and suppressing and delaying DNA damage repair induced by the radiation, and completed the present disclosure.